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Background: Prospective data on red and processed meat in relation to risk of subtypes of esophageal and gastric cancer are scarce. We present analyses of association between red and processed meat and the risk of esophageal and gastric cancer subtypes within The Netherlands Cohort Study on Diet and Cancer. Design: 120 852 individuals aged 55-69 years were recruited in 1986, and meat intake was assessed using a 150-item food frequency questionnaire. After 16.3 years of follow-up, 107 esophageal squamous cell carcinomas, 145 esophageal adenocarcinomas, 163 gastric cardia adenocarcinomas, 489 gastric non-cardia adenocarcinomas, and 3923 subcohort members were included in a case-cohort analysis. Results: Processed as well as red meat intake was positively associated with esophageal squamous cell carcinoma in men. Hazard ratios for highest versus lowest quintile of processed and red meat were 3.47 [95% confidence intervals (CI): 1.21-9.94; P for trend: 0.04] and 2.66 (95% CI: 0.94-7.48; P for trend: 0.06), respectively. No association was seen for adenocarcinomas or gastric cancer subtypes or for any of the four subtypes among women. Conclusion: Our findings suggest that red and processed meat consumption is associated with increased risk of esophageal squamous cell carcinoma in men but not with cancers of other esophageal and gastric subtypes. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

The association between vegetable and fruit consumption and stomach cancer risk was investigated in the Netherlands Cohort Study among 120,852 men and women aged 55-69 years at the start in September 1986. Analyses were based on 282 incident stomach cancer cases after 6.3 years of follow-up. Age- and sex-adjusted rate ratios of stomach cancer in increasing quintiles of combined vegetable and fruit consumption were 1.00, 0.70, 0.65, 0.76, and 0.64 (p trend = 0.04). Multivariate analysis resulted in rate ratios that were somewhat closer to one (p trend = 0.14). Furthermore, inverse associations for total vegetables, pulses, raw leafy vegetables, total fruit, citrus fruit, and apples and pears that were observed in crude analyses became weaker or disappeared in multivariate analyses. Total vegetable, but not fruit, consumption was significantly lower in cases diagnosed in the first follow-up year. In analyses limited to first year cases (resembling a case-control study), rate ratios for increasing tertiles of total vegetable consumption were 1.00, 0.17, and 0.18 (p trend = 0.0001), which may indicate the presence of information bias in case-control studies. This prospective study suggests that vegetable and fruit consumption was not clearly associated with stomach cancer risk in the Dutch population. The findings of this study are comparable with findings of other cohort studies, but they do not support the findings of case-control studies.

Background: Tea is one of the most frequently consumed beverages in the world. Antioxidant polyphenol compounds (such as catechins and flavonols) are abundantly present in both green and black teas and have been observed to have anticarcinogenic properties in cell and animal model studies. In black tea, however, most of the catechins have been oxidized to forms that may have reduced anticarcinogenic properties. Despite indications from experimental studies that tea may protect against cancer, epidemiologic evidence has been inconclusive. Purpose: The association between black tea consumption and the subsequent risk of stomach, colorectal, lung, and breast cancers was investigated in The Netherlands Cohort Study on Diet and Cancer among 58 279 men and 62 573 women aged 55-69 years. Methods: Subjects in the cohort completed a self-administered questionnaire on dietary habits and other risk factors for cancer at base line in 1986. Follow-up for cancer was done by means of computerized record linkage with all nine regional cancer registries in The Netherlands and the national pathology database. During 4.3 years of follow-up, 200, 650, 764, and 650 cases of stomach, colorectal, lung, and breast cancers were diagnosed, respectively. The questionnaire data of case subjects and those of a random subcohort (n = 3500) were used to calculate rate ratios (RRs) of cancer in categories of consumers of black tea compared with nonconsumers. Results: Tea was not used by 13% of the subjects in the cohort, whereas 37%, 34%, and 16% consumed one to two, three to four, and five or more cups of tea per day, respectively. No association was observed between tea consumption and risk of colorectal cancer: The risk among tea drinkers in each consumption category was similar to that among nondrinkers. The RR of breast cancer among consumers of five or more cups of tea per day was 1.3 (95% confidence interval = 0.9-2.0); no dose-response association was observed. In age- and sex-adjusted analyses, consumption of tea was inversely associated with stomach (two-sided P for trend = .147) and lung (two-sided P for trend <.001) cancers. However, tea drinkers appeared to smoke less and to eat more vegetables and fruits than nondrinkers. When smoking and dietary factors were taken into account, tea in itself did not appear to protect against stomach and lung cancers: The RRs in all consumption categories were close to unity. Analysis of the tea and cancer relationship in a subgroup that included subjects in the lowest two quintiles of consumption of vegetables and fruits also failed to reveal a protective effect of tea consumption on the risk of three cancer types studied (colorectal, lung, and breast cancers). Conclusions: This investigation does not support the hypothesis that consumption of black tea protects against four of the major cancers in humans; a cancer-enhancing effect was not evident, either.

Biomarkers have considerable potential in aiding the understanding of the relationship between diet and disease or health. However, to assess the role, relevance and importance of biomarkers on a case by case basis it is essential to understand and prioritise the principal diet and health issues. In the majority of cases, dietary compounds are only weakly biologically active in the short term, have multiple targets and can be both beneficial and deleterious. This poses particular problems in determining the net effect of types of foods on health. In principle, a biomarker should be able to contribute to this debate by allowing the measurement of exposure and by acting as an indicator either of a deleterious or of an enhanced health effect prior to the final outcome. In this review, the examples chosen - cancer (stomach, colon/rectal, breast); coronary heart disease and osteoporosis - reflect three major diet-related disease issues. In each case the onset of the disease has a genetic determinant which may be exacerbated or delayed by diet. Perhaps the most important factor is that in each case the disease, once manifest, is difficult to influence in a positive way by diet alone. This then suggests that the emphasis for biomarker studies should focus on predictive biomarkers which can be used to help in the development of dietary strategies which will minimise the risk and be of greater benefit. Chemicals/CAS: Biological Markers; Tumor Markers, Biological

Both carcinogenic and anticarcinogenic properties have been reported for the synthetic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). The association between dietary intake of BHA and BHT and stomach cancer risk was investigated in the Netherlands Cohort Study (NLCS) that started in 1986 among 120,852 men and women aged 55 to 69 years. A semi-quantitative food frequency questionnaire was used to assess food consumption. Information on BHA or BHT content of cooking fats, oils, mayonnaise and other creamy salad dressings and dried soups was obtained by chemical analysis, a Dutch database of food additives (ALBA) and the Dutch Compendium of Foods and Diet Products. After 6.3 years of follow-up, complete data on BHA and BHT intake of 192 incident stomach cancer cases and 2035 subcohort members were available for case-cohort analysis. Mean intake of BHA or BHT among subcohort members was 105 and 351 μg/day, respectively. For consumption of mayonnaise and other creamy salad dressings with BHA or BHT no association with stomach cancer risk was observed. A statistically non-significant decrease in stomach cancer risk was observed with increasing BHA and BHT intake [rate ratio (RR) highest/lowest intake of BHA=0.57 (95% confidence interval (CI): 0.25-1.30] and BHT=0.74 (95% CI: 0.38-1.43). In this study, no significant association with stomach cancer risk was found for usual intake of low levels of BHA and BHT. Copyright (C) 2000 Elsevier Science Ltd. Chemicals/CAS: Antioxidants; Butylated Hydroxyanisole, 25013-16-5; Butylated Hydroxytoluene, 128-37-0; Food Additives

Objective: Many case-control studies have reported that salt and cured meat intake are positively, and refrigerator use is inversely, associated with stomach cancer risk. In the current prospective study these associations were evaluated. Methods: The Netherlands Cohort Study consisted of 120,852 men and women ages 55-69 years at baseline in 1986. Salt exposure was measured by calculating mean daily sodium intake (dietary salt) from 150 food items and by specific salt questions. After 6.3 years of follow-up, 282 incident stomach cancer cases were available for analyses. Case-cohort analyses were based on the 282 cases and 3123 subcohort members. Results: In multivariate analyses adjusted for age, sex, smoking, education, stomach disorders, history of stomach cancer in the family, rate ratios (RR) for increasing quintiles of energy-adjusted intake of dietary salt were 1.00, 1.49, 1.03, 1.54 and 1.18, respectively (p trend = 0.43). An inverse association was found between stomach cancer and salt added at the hot meal (p trend = 0.04). For salt added to home-made soup, use of salt at the table, salt preference and duration of refrigerator use, no associations were observed. Positive associations were found for bacon (RR highest/lowest intake = 1.33; 95% CI = 1.03-1.71) and other sliced cold meat (RR highest/lowest intake = 1.29; 95% CI = 0.96-1.72), but not for smoked sausage, total cold meats, rashers/bacon, boiled ham and smoked beef/pork loin roll. Separate analyses among subjects with self-reported stomach disorders revealed higher RR of stomach cancer for dietary salt and several types of cured meat. Conclusion: The present findings suggest that intake of dietary salt and several types of cured meat were weakly positively associated with stomach cancer risk.

Proteinases are involved in tumour invasion and metastasis. Several matrix metalloproteinases (MMPs) have been shown to be increased in various human carcinomas. We assessed the levels of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in 50 gastric carcinomas and corresponding mucosa using quantitative gelatin zymography. Both MMP levels were significantly enhanced in gastric carcinomas compared with adjacent mucosal tissue, showed a relatively poor intercorrelation and no relation was found with histopathological carcinoma classifications according to Lauren, WHO and tumour-node-metastasis (TNM). Cox's multivariate proportional hazards analyses revealed that high carcinomatous MMP values are of prognostic significance for a poor overall survival of the patients, independent of the major clinicopathological parameters. Chemicals/CAS: Collagenases, EC 3.4.24.-; Gelatinases, EC 3.4.24.-; Matrix Metalloproteinase 2, EC 3.4.24.24; Matrix Metalloproteinase 9, EC 3.4.24.35; Metalloendopeptidases, EC 3.4.24.-

This paper gives an overview of the epidemiological data concerning the cancer-preventive effect of brassica vegetables, including cabbage, kale, broccoli, Brussels sprouts, and cauliflower. The protective effect of brassicas against cancer may be due to their relatively high content of glucosinolates. Certain hydrolysis products of glucosinolates have shown anticarcinogenic properties. The results of 7 cohort studies and 87 case control studies on the association between brassica consumption and cancer risk are summarized. The cohort studies showed inverse associations between the consumption of cabbage, cauliflower, and broccoli and risk of lung cancer; between the consumption of brassicas and risk of stomach cancer; between broccoli consumption and risk of all cancers taken together; and between brassica consumption and the occurrence of second primary cancers. Of the case-control studies, 67% showed an inverse association between consumption of total brassira vegetables and risk of cancer at various sites. For cabbage, broccoli, cauliflower, and Brussels sprouts, these percentages were 70, 56, 67, and 29%, respectively. Although the measured effects might have been distorted by various types of bias, it is concluded that a high consumption of brassica vegetables is associated with a decreased risk of cancer. This association appears to be most consistent for lung, stomach, colon, and rectal cancer and least consistent for prostatic, endometrial, and ovarian cancer. It is not yet possible to resolve whether associations are to be attributed to brassica vegetables per se or to vegetables in general. Further epidemiological research should separate the anticarcinogenic effect of brassica vegetables from the effect of vegetables in general.

Background: In the last decades, the incidence of oesophageal and gastric cardia adenocarcinoma has increased rapidly in the Western world. We investigated the association between body mass index (BMI), height and risk of oesophageal and gastric cardia adenocarcinoma. Methods: The Netherlands Cohort Study was initiated in 1986. All participants (n = 120 852), aged 55-69 years, completed a self administered questionnaire. Cases were identified through annual record linkage with the Netherlands Cancer Registry. After 13.3 years of follow-up, excluding the first follow-up year, complete data from 4552 subcohort members, 133 oesophageal and 163 gastric cardia adenocarcinomas were available for case-cohort analyses. Incidence rate ratios (RRs) and corresponding 95% confidence intervals were estimated using Cox proportional hazard models. Results: The RRs (95% CI) of oesophageal adenocarcinoma were 1.40 (0.95 to 2.04) and 3.96 (2.27 to 6.88) for overweight (BMI 25.0-29.9 kg/m2) and obese subjects (BMI ≥ 30.0 kg/m2), respectively, compared to subjects with normal weight (BMI 20.0-24.9 kg/m2). For gastric cardia adenocarcinoma, these RRs were 1.32 (0.94 to 1.85) and 2.73 (1.56 to 4.79). Also change in BMI during adulthood was positively associated with the risk of oesophageal and gastric cardia adenocarcinoma (p trend 0.001 and 0.02, respectively), while no association was found with BMI in early adulthood (p trend 0.17 and 0.17, respectively). None of the tumour types investigated was significantly associated with height. Conclusions: These results confirm higher risks of oesophageal and gastric cardia adenocarcinoma with increasing BMI. This implies that the increasing prevalence of obesity may be one of the explanations for the rising incidence of oesophageal and gastric cardia adenocarcinoma in the Western world.

The association between the intake of nitrate or nitrite and gastric cancer risk was investigated in a prospective cohort study started in 1986 in the Netherlands, of 120,852 men and women aged 55-69 years. At baseline, data on dietary intake, smoking habits and other covariates were collected by means of a self-administered questionnaire. For data analysis, a case-cohort approach was used, in which the person-years at risk were estimated from a randomly selected subcohort (1688 men and 1812 women). After 6.3 years of follow-up, 282 microscopically confirmed incident cases of stomach cancer were detected: 219 men and 63 women. We did not find a higher risk of gastric cancer among people with a higher nitrate intake from food [rate ratio (RR) highest/lowest quintile = 0.80, 95% CI 0.47-1.37, trend-P = 0.18], a higher nitrate intake from drinking water (RR highest/lowest quintile = 0.88, 95% CI 0.59-1.32, trend-P = 0.39) or a higher intake of nitrite (RR highest/lowest quintile = 1.44, 95% CI 0.95-2.18, trend-P = 0.24). Rate ratios for gastric cancer were also computed for each tertile of nitrate intake from foods within tertiles of vitamin C intake and intake of beta-carotene, but no consistent pattern was found. Therefore, our study does not support a positive association between the intake of nitrate or nitrite and gastric cancer risk.

Prospective epidemiologic data on vegetables and fruits consumption and risk of subtypes of esophageal and gastric cancer are sparse. We studied the association between vegetables and fruits consumption and risk of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA) and gastric noncardia adenocarcinoma (GNCA) in the Netherlands Cohort Study. In 1986, 120,852 Dutch men and women aged 55-69 filled out a questionnaire on diet and other cancer risk factors. After 16.3 years of follow-up, 101 ESCC, 144 EAC, 156 GCA, 460 GNCA cases and 4,035 subcohort members were available for case-cohort analysis using Cox proportional hazards models. Multivariable adjusted incidence rate ratios (RRs) were generally below unity. Total vegetable consumption was nonsignificantly inversely associated with EAC and ESCC risk, but not with GCA and GNCA risk. Significant inverse associations were observed for raw vegetables and EAC risk [RR per 25 g/day: 0.81, 95% confidence interval (CI) 0.68-0.98], and Brassica vegetables and GCA risk (RR per 25 g/day: 0.72, 95% CI 0.54-0.95). Total fruit consumption was associated with a nonsignificantly decreased EAC risk. Citrus fruits were inversely associated with EAC and GCA risk (RRs for highest vs. lowest intake: 0.55, 95% CI 0.31-0.98 and 0.38, 95% CI 0.21-0.69, respectively). Specifically for current smokers, vegetables and possibly also fruits intake was inversely associated with ESCC and EAC risk. Consumption of (specific groups of) vegetables and fruits may protect against subtypes of esophageal and gastric cancer. Copyright © 2011 UICC.

Study objective - To study the association between socioeconomic status (SES) and stomach cancer incidence (cardia and non-cardia) and the role of lifestyle factors in explaining this association. Design - Prospective cohort study on diet and cancer that started in 1986. Data were collected by means of a self administered questionnaire. Setting - Population originating from 204 municipalities in the Netherlands. Participants - 58 279 men aged 55-69 years. After 4.3 years of follow up, 162 incident stomach cancer cases were detected (49 cardia and 113 non-cardia cases). Main results and conclusions - After adjustment for age, a lower overall stomach cancer risk was found for men with the highest attained level of education (RR highest/lowest level = 0.54, 95% CI 0.33, 0.89, trend, p = 0.02). This association became less strong after additional adjustment for smoking, intake of vitamin C, β carotene, alcohol and coffee, family history of stomach cancer, and history of stomach disorders (RR = 0.61, 95% CI 0.34, 1.07, trend, p = 0.11). No clear association was found between occupation based SES indicators and stomach cancer risk. Analyses per subsite of stomach cancer revealed that for people with the highest level of education the age adjusted rate ratio for cardia cancer changed from 0.37 (95% CI = 0.13, 1.00) to 0.60 (95% CI = 0.19, 1.87) after additional adjustment for lifestyle variables, whereas the rate ratio for non-cardia cancer (RR = 0.59, 95% CI 0.33, 1.05) did not change after additional adjustment.

BACKGROUND. Numerous components of fruit and vegetables are considered to decrease the risk of gastric carcinoma. In the current prospective study, the authors examined the association between the intake of vitamins, carotenoids, and dietary fiber and vitamin supplement use and the incidence rate of gastric carcinoma. METHODS. The Netherlands Cohort Study began in 1986 with 120,852 men and women ages 55-69 years. Data regarding diet and other covariates were collected by means of a self-administered questionnaire. After 6.3 years of follow-up, data regarding 282 incident cases of gastric carcinoma and 3123 subcohort members were available for case-cohort analyses. RESULTS. In analyses adjusted for age, gender, smoking history, education, stomach disorders, and family history of gastric carcinoma, an inverse association with vitamin C intake (relative risk [RR] for highest vs. lowest intake category, 0.7; 95% confidence interval [95% CI], 0.5-1.0) was observed, with a borderline significant trend across three intake categories (P = 0.06). After the exclusion of cases diagnosed in the first and second follow-up years, the RR was 0.9 (95% CI, 0.6-1.2; P trend = 0.44). Intake of retinol and β-carotene were associated positively with gastric carcinoma risk with highest versus lowest quintile RRs of 1.6 (95% CI, 1.0-2.5; P trend = 0.02) and 1.6 (95% CI, 1.0-2.6; P trend = 0.13), respectively, after the exclusion of first-year and second-year cases. Intake of folate, vitamin E, α-carotene, lutein plus zeaxanthin, β-cryptoxanthin, lycopene, and dietary fiber was not associated with gastric carcinoma. Patients who used vitamin A-containing supplements had a lower risk of gastric carcinoma than nonusers (RR = 0.4; 95% CI, 0.2-0.9). CONCLUSIONS. No clear inverse associations were found between the intake of vitamins, carotenoids, and dietary fiber and the risk of gastric carcinoma after adjustment for confounding variables and the exclusion of first-year and second-year cases. (C) 2000 American Cancer Society. Chemicals/CAS: Anticarcinogenic Agents; Ascorbic Acid, 50-81-7; Carotenoids, 36-88-4; Vitamin A, 11103-57-4; Vitamin E, 1406-18-4; Vitamins

Transforming growth factor-β1 (TGF-β1), a tumour suppressing as well as tumour-promoting cytokine, is stored as an extracellular matrix-bound latent complex. We examined TGF-β1 activation and localisation of TGF-β1 activity in gastric cancer. Gastric tumours showed increased stromal and epithelial total TGF-β1 staining by immunohistochemistry. Active TGF-β1 was present in malignant epithelial cells, but most strongly in smooth muscle actin expressing fibroblasts. Normal gastric mucosa from the same patient showed some staining for total, and little for active TGF-β1. Active TGF-β1 levels were determined by ELISA on tissue homogenates, confirming a strong increase in active TGF-β1 in tumours compared to corresponding normal mucosa. Moreover, high tumour TGF-β1 activity levels were significantly associated with clinical parameters, including worse survival of the patients. Total and active TGF-β1 levels were not correlated, suggesting a specific activation process. Of the different proteases tested, active TGF-β1 levels were only correlated with urokinase activity levels. The correlation with urokinase activity suggests a role for plasmin in TGF-β1 activation in the tumour microenvironment, resulting in transformation of resident fibroblasts to tumour promoting myofibroblasts. In conclusion we have shown localisation and clinical relevance of TGF-β1 activity levels in gastric cancer. © 2007 Cancer Research.

Diet has been hypothesized to play a role in the etiology of gastrointestinal cancer for a long time. Initially, strong evidence of such effects was found in retrospective epidemiological studies. Dietary habits, in particular those from the distant past, are difficult to measure, however. Results from recent, prospective and larger studies of better quality did not always confirm these associations. Consumption of fruits and vegetables appear to have a modest role in the prevention of gastrointestinal cancers. In contrast, the roles of alcohol consumption and overweight on risk of gastrointestinal cancer have become much clearer. Overweight and obesity are important risk factors for adenocarcinoma (but not squamous carcinoma) of the esophagus, gastric cardia carcinoma (but not noncardia carcinoma), and colorectal cancer, the latter in particular among men. Alcohol consumption is a risk factor for squamous carcinoma (but not adenocarcinoma) of the esophagus, gastric cancer and colorectal cancer. Selenium may be inversely related to esophageal and gastric cancer. © 2006 Elsevier Ltd. All rights reserved.

In a pioneer study, we showed 10 years ago that enhanced tissue levels of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in gastric cancers, as determined by zymography, were related with worse overall survival of the patients. To corroborate these observations, we now assessed MMP-2 and MMP-9 with new techniques in an expanded group of gastric cancer patients (n = 81) and included for comparison MMP-7, MMP-8 and the tissue inhibitors of MMPs, TIMP-1 and -2. All MMPs and TIMP-1 were significantly increased in tumour tissue compared to normal gastric mucosa. Matrix metalloproteinase-7, -8 and -9, and the TIMPs showed some correlations with the clinicopathologic parameters TNM, WHO and Laurén classification, but their levels were not related with survival. Regardless of the determination method used, that is, enzyme-linked immunosorbent assay or bioactivity assay, an enhanced tumour MMP-2 level did not show a significant correlation with any of the clinicopathological parameters, but was confirmed to be an independent prognostic factor in gastric cancer. © 2006 Cancer Research. Chemicals / CAS: gelatinase A, 146480-35-5; gelatinase B, 146480-36-6; matrilysin, 141256-52-2; tissue inhibitor of metalloproteinase 1, 140208-24-8; tissue inhibitor of metalloproteinase 2, 124861-55-8; Matrix Metalloproteinase 2, EC 3.4.24.24